Scleroderma (systemic sclerosis) is a generalized disorder characterized by intense scarring of the skin, lungs, gut, heart and kidneys; closely associated with this interstitial fibrosis is an intimal vascular and microvascular lesion throughout the body characterized by endothelial perturbation, intimal proliferation (smooth muscle cells), mononuclear cell infiltrates in the perivascular region, and vascular insufficiency of critical organ function which defines the prognosis and outcome in the individual patient. Increased understanding of scleroderma, which is the third most prevalent rheumatic disease (after rheumatoid arthritis and lupus) and which forms the bedrock for a number of diffuse connective tissue disorders (overlap syndromes, undifferentiated connective tissue syndromes (UCTS), mixed connective tissue disease (MCTD), Sjogren's associated syndromes, etc.), has come from study of the target cells (fibroblasts, smooth muscle cells, endothelial cells), from the matrix proteins synthesized and secreted, from serum activity studies, from serological studies of antinuclear and antimatrix antibodies, and from studies of immune cells and related cytokines (interleukins, interferons). We will study the growth regulation and gene expression of the scleroderma fibroblast and the interaction of endothelial cells with characterized recombinant cytokines, with serum activities, and with mononuclear cell and lymphocyte interactions relevant to the vascular and fibrotic manifestations of this untreatable and essentially incurable disease. We propose an in-depth cellular and molecular analysis of scleroderma; the hypothesis is that target cells are persistently activated and that the gene expression of this activation state can be studied directly by techniques of transfection, gene isolation, and gene sequencing to determine the molecular basis of abnormal competence or growth regulation genes in scleroderma. By studies combining several disciplines, we hope to integrate the presently disparate findings in this disease toward a logical and effective therapeutic intervention.